Human liver cancer, with increasing occurrence in the United States, is the 5th most prevalent malignant disease in the world. It is the fourth leading cause of cancer mortality, which accounts for an estimated 1 million deaths annually. Hepatocellular carcinoma (HCC) is a major type of primary liver cancer. HCC is considered to be a terminally ill disease and currently, there is little progress toward the discovery of efficient therapies leading to regression. This is due largely to the lack of a method for early diagnosis and the lack of information on the phenotypic changes associated with the development of HCC. Our goals are to identify common gene clusters that are responsible for the genesis of HCC and to discover new genes critical for viral hepatitis-mediated HCC as well as genes necessary for metastasis. For example, by comparing liver samples from chronic liver disease patients with varying degrees of risk for developing hepatocellular carcinoma, we have identified unique fingerprints that may be useful in diagnosing patients with early onset of liver cancer. By comparing hepatocellular carcinoma with or without accompanying metastasis, we have identified a molecular signature that can be used to predict liver cancer patients with a potential to develop metastasis or recurrence. In addition, we are examining the role of the liver microenvironment in metastasis and recurrence by focusing particularly on the functions of immune cells and the inflammatory process in liver cancer progression. We have also identified several potential therapeutic targets that may be used to eliminate liver cancer cells or stop metastatic progression. Currently, we are exploring the roles of these genes in liver cancer initiation and metastasis. Our findings have been extremely fruitful as they may not only offer utilities to patient managements, but also challenge the current paradigm of tumor evolution. Clearly, gene expression profiling has expanded our knowledge of the global changes that occur in liver cancer, and has provided numerous insights into the molecular mechanisms of this disease. In addition, these studies will undoubtedly contribute to the establishment of novel markers with potential diagnostic and prognostic value, as well as potential therapeutic targets for direct clinical intervention of this disease.